The theme of this program project is the inter-relation of mechanics, chemistry and hydrodynamics as underlying mechanisms in normal and pathological peripheral vascular function. Abnormalities in peripheral vascular function are integral to the pathology associated with the most serious diseases in Western society, including heart disease, stroke and cancer metastasis, and also play a fundamental role in less serious disorders involving inflammation and immune response. Four project are engaged in synergistic studies designed to reveal fundamental mechanisms underlying both normal and pathological phenomena in the peripheral vasculature. Dr. Hammer's project focuses on the chemical and hydrodynamic factors that govern interactions between neutrophils and endothelium, particularly on the role of cell-cell interactions and differences between in vitro studies, from which most of our current understanding comes, and clinically relevant events in vivo. The next project focuses on the important role that ion transport plays in neutrophils during cell activation in response to inflammatory agents and on the consequences of changes in ion transport on neutrophil adhesion and rheology, as well as on volume regulation in endothelial cells particularly under conditions of ischemia, and on the consequences of failed endothelial cell volume regulation in ischemia-reperfusion injury. The next project focused on the development of red cell membrane mechanical stability during erythropoiesis and the consequences of abnormal red cell deformability on cell function in the vasculature, as well as on the role of impingement and detachment forces in modulating neutrophil adhesive behavior. The final project focuses on the mechanisms underlying flow heterogeneities in the microvasculature, particularly on the consequences of abnormal red cell deformability on cell flux and microvascular flow, on the effects of changing vessel geometry on flow distribution and on mechanisms underlying heterogeneities in leukocyte distribution and behavior. The integration of these studies will result in improve understanding of basic mechanisms related to normal and pathological process within the peripheral vasculature, and could lead to the development of new strategies to relieve pathological conditions related to clinical disorder resulting from abnormalities in these processes.